https://hdl.handle.net/10481/74574 Tue, 07 Apr 2026 01:48:46 GMT 2026-04-07T01:48:46Z https://hdl.handle.net/10481/83675 Structure - activity studies with histamine H3 - receptor ligands Ganellin, C. R.; Fkyerat, A.; Hosseini, S. K.; Khalaf, Y. S.; Piripitsi, A.; Tertiuk, W.; Arrang, J. M.; Garbarg, M.; Ligneau, X.; Schwartz, J. C. Se han sintetizado análogos de tioperamida. Los compuestos han sido ensayados in vitro para explorar los factores que permitan diseñar compuestos derivados de la tioperamida sin grupo tiourea que mejoren la penetración cerebral. Los compuestos más activos como H3-antagonistas contienen un átomo de nitrógeno aromático hetorocíclico sobre la cadena lateral. Estos compuestos se han empleado como cabeza de serie para obtener potentes H3-antagonistas de histarnina con estructura de ariloxietil y ariloxipropilimidazoles. Las relaciones estructura actividad de agonistas se han revisado brevemente. Se han estudiado un grupo de análogos de (S-[2-imidazol-4-il)etil]isotiourea (imetit) con el objeto de explorar la transición entre agonistas y antagonistas. N,N' -dibutil-[S-[3-(imidazol- 4-il)propil]isotiourea es un muy potente antagonistas que tiene Ki=1.5 nM.; Analogues of thioperamide have been synthesised and tested in vitro on rat cerebral cortex to explore structure-activity relationships with the intention of designing compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. Compounds derived from histamine and having an aromatic nitrogen containing heterocyc1e on the side-chain amino group have been found to act as H3 - antagonists. These have served as leads to provide aryloxyethyl- and aryloxypropylimidazoles which are potent H3 antagonists of histamine. Structure-activity relationships for agonists are brief1y reviewed. Analogues of the very potent and selective agonist, imetit (S-[2-imidazol-4-yl)ethyl]isothiourea) have been studied to explore the transition between agonist, partial agonist and antagonist. The isosteric isourea is also a potent agonist. N,N' -Dibutyl-[S-[3-(imidazol-4-yl)propyl]isothiourea is a very potent antagonist having K¡=1.5 nM. https://hdl.handle.net/10481/83675 https://hdl.handle.net/10481/83673 A stereodivergent access to naturally occurring aminocarbasugars from (Phenylsulfonyl)-7 -oxa-bicyclo[2.2.1 ]heptane derivatives. Total synthesis of ( + )-Validamine and its CI and C2 stereoisomers Arjona, O.; Plumet, J. The total syntheses of the antibiotic validamine an its three diastereomers have been acomplished and their racemic penta-N-O-acetates via stereocontrolled nucleophilic epoxidation of polihydroxylated cyclohexenyl sulfones, obtained from (phenylsulphonyl)-7- oxabicyclo[2,2, l ]heptanes. The diastereoselectivity of the epoxidation can be readily controlled by careful choice of the hydroxyl protecting group. Ring opening of the resulting epoxisulfones followed by stereocontrolled introduction of an amine precursor led to the four C-l and C-2 diastereomers of the I-aminocarbasugars.; La epoxidación nucleofilica estereocontrolada de ciclohexenil sulfonas polidroxiladas, obtenidas a partir de (fenilsulfonil)-7-oxabiciclo[2,2, l ] heptano s conduce a la síntesis total del antibiótico validarnina y sus tres diastereoisómeros. La diastereoselectividad de la epoxidación puede controlarse facilrnente mediante la elección del grupo protector del hidroxilo. La apertura del anillo de las epoxisulfonas resultantes, seguida de la introduc ción estereocontrolada de un precursor del grupo https://hdl.handle.net/10481/83673 https://hdl.handle.net/10481/83672 New developments in opioid receptors ligands Ronsisvalle, G.; Prezzavento, O.; Pasquinucci, L.; Marazzo, A.; Vittorio, F.; Pappalardo, M. S.; Bousquet, E. Relevant developments have been achieved in the last twenty years in the search for opioid agonists and antagonists with selectivity for each receptor subpopulation. Recently, new benzomorphan derivatives have been synthesized and compounds with substituted cyclopropylmethyl functionalities at N-l position showed high affinity and selectivity for K opioid receptor subpopulations. MPCB and CCB were selected as specific K agonists. The affinity ofCCB was two-fold the USO,488H one. Mixed peptide-heterocyclic compounds have been derived from these compounds and important informations on binding processes of K ligands have been obtained.; En los últimos veinte años se ha llevado a cabo una intensa investigación sobre la búsqueda de agonistas y antagonistas selectivos de cada subtipo de receptores opiáceos. Recientemente, se han sintetizado nuevos derivados benzomorfánicos y compuestos con restos ciclopropilmetílicos sobre N-l que muestran alta afinidad y selectividad por los receptores K . Los compuestos MPCB y CCB se han seleccionado como agonistas específicos K. La afinidad de CCB es dos veces mayor que la del compuesto USO,488H. De estos compuestos se han derivado interesantes compuestos con estructura de peptidoheterocido y se han obtenido importantes informaciones sobre los procesos de binding a los receptores K. https://hdl.handle.net/10481/83672 https://hdl.handle.net/10481/83671 Past approaches to discovering new medicines Ganellin, C.; Robin, C. Se hace una breve historia de las principales aproximaciones al descubrimiento de nuevos fármacos. Se describen cuatro de las principales aproximaciones: productos naturales, uso de prototipos existentes, screening farmacológico y transmisores fisiológicos.; A brief account is given of the main approaches to new drug discovery which have been taken during the twentieth century. Four main sources for new drugs are described and each of these is discussed in turn; they are: natural products, existing drugs, screens and physiological transmitters. https://hdl.handle.net/10481/83671 https://hdl.handle.net/10481/74598 Sulfone directed alkylative bridge cleavage of oxabicyclic vinyl sulfones with organolithium reagents (1) Arjona, O.; Plumet, J. An efficient regio- and stereocontrolled methodology for the alkylative bridge cleavage of oxabicyclic vinyl sulfones is described. A range of 7 -oxabicyclic[2.2.1. ]heptenyl and 8-oxabicyclic [3.2.1.]octenyl sulfones has been found to undergo an overall syn S~' opening when treated with a wide variety of organolithium reagents and lithium aluminum hydride. In this manner, higWy functionalized cyclohexenyl and cycloheptenyl sulfones, versatile synthetic intermediates, are now available in high yields. The complete stereoselectivity encountered in the exo conjugate addition may be explained by chelation of the organometallic reagent with the oxygen bridge and steric factors. Furthermore, less-strained substrates allow for complete control of the addition and elimination stages.; Se describe una interesante rotura alquilante regio-y estereocontrolada del puente de oxabiciclo vinil sulfonas. Las 7-oxabiciclo[2.2.1] heptenil y 8-oxabiciclo [3.2.1.] octenil sulfonas sufren aperturas syn S~' cuando se tratan con una amplia variedad de reactivos organolíticos e hiduro de litio y aluminio. De esta forma, se obtienen ciclohexenil y cicloheptenil sulfonas, altamente funcionalizadas, que son intermedios sintéticos versátiles. La completa estereoselectividad encontrada en la adición conjugada exo puede explicarse en base a la quelación del reactivo organometálico con el oxígeno puente. This research was supported by D.G.I.C.Y.T. (Grant no. PB90-0035) and PharmaMar S.A. (Madrid). We are grateful to the Comunidad Autónoma Madrid and the Universidad Complutense de Madrid for doctoral fellowships A. d. D. and A. V. respectively. https://hdl.handle.net/10481/74598